Ursodeoxycholic acid is a bile acid wherein hydroxyl groups are located at the 3.alpha. and 7.beta. positions of the steroid molecule and has the structural formula (I) shown below. ##STR1##
Ursodeoxycholic acid is known as one of the traditional cholagogues. Since it was discovered that this material is effective to solubilize cholesterol gallstones, plenty of clinical data have been reported to show that the material is effective for therapy of cholesterol gallstone per os administration.
Since ursodeoxycholic acid is available in the bile of a bear, it is possible to extract it therefrom. It is unrealistic, however, to assume that the supply is sufficient to meet the entire medical demands particularly from the quantitative viewpoint. Accordingly, chemical synthesis processes have been employed for production of ursodeoxycholic acid.
One exemplary process for synthesis of ursodeoxycholic acid will be described below.
The first step is to methylate the carboxyl group of cholic acid (II), the starting material, the converting cholic acid (II) to methyl cholate (III), as shown below. ##STR2##
The second step is to acetylate the hydroxyl groups located at the 3.alpha. and 7.alpha. positions of methyl cholate (III) by adding acetic anhydride to the same to obtain 3.alpha.,7.alpha.-diacetoxy-12.alpha.-hydroxy-5.beta.-methyl cholanate (IV), as shown below. ##STR3##
The third step is to oxidize the hydroxyl group located at the 12 position of 3.alpha.,7.alpha.-diacetoxy-12.alpha.-hydroxy-5.beta.-methyl cholanate (IV) by adding chromic acid to the same to obtain 3.alpha.,7.alpha.-diacetoxy-12-keto-5.beta.-methyl cholanate (V), as shown below. ##STR4##
The fourth step is to saponify 3.alpha.,7.alpha.-diacetoxy-12-keto-5.beta.-methyl cholanate (V) to obtain 12-ketochenodeoxycholic acid (VI), as shown below. ##STR5##
The fifth step is to reduce the carbonyl group located at the 12 position of 12-ketochenodeoxycholic acid (VI) by employing the Huang-Minlon modification to obtain chenodeoxycholic acid (VII), as shown below. ##STR6##
The sixth step is to oxidize the hydroxyl group located at the 7.alpha. position of chenodeoxycholic acid (VII) by adding N-bromosuccinimide to the same, thus obtaining 7-ketolithocholic acid (VIII), as shown below. ##STR7##
The seventh or final step is to reduce 7-ketolithocholic acid (VIII) under a catalytic reduction process carried out in n-butanol, thus obtaining the final product, ursodeoxycholic acid (I), as shown below. ##STR8##
Since the foregoing process for production of ursodeoxycholic acid available in the prior art comprises 7 independent steps each of which requires a purification process thereafter, the process has various drawbacks such as being complicated, insufficient productivity, etc.
Further, the process results in a low yield caused by various undesirable side reactions which are likely to accompany each of the foregoing independent steps.